Diuretic and saluretic composition and method containing 5-(2-methylene-alkanoyl)-benzofuran compounds

ABSTRACT

A method of producing a diuretic and saluretic effect in mammals comprising administering 5-(2-methylene-alkanoyl)-benzofuran compounds to said mammals and pharmaceutical compositions containing said compounds. A typical embodiment is 5-(2methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid.

United States Patent Zerginyi et a].

[ 51 3,681,502 [451 Aug. 1,1972

[54] DIURETIC AND SALURETIC COMPOSITION AND METHOD CONTAININGS-(Z-METHYLENE- ALKANOYL)-BENZOFURAN COMPOUNDS [72] Inventors: JanosZerginyi, Riehen; Ernst Habicht, Oberwil, both of Switzerland [73]Assignee: Ciba-Geigy Corporation, Ardsley,

[52] US. Cl. ..424/285, 424/244, 424/274 [51] Int. Cl. ..A0ln 9/28, A6lk27/00 58 Field of Search ..424/274, 244, 285

[56] References Cited UNITED STATES PATENTS 2,680,119 6/1954 Robertson..260/346.2 3,394,125 7/1968 Crenshaw ..424/285X Primary Examiner-AlbertT. Meyers Assistant Examiner-Dale R. Ore Attorney-Karl F. Jorda andBruce M. Collins [5 7] ABSTRACT A method of producing a diuretic andsaluretic effect in mammals comprising administering5-(2-methylenealkanoyl)-benzofuran compounds to said mammals andpharmaceutical compositions containing said compounds. A typicalembodiment is 5-(2-methylenebutyryl)-6-methyl-benzofuran-2-carboxylicacid.

20 Claims, No Drawings DIURETIC AND SALURETIC COMPOSITION AND METHODCONTAINING -(2-METHYLENE- ALKANOYL)-BENZOFURAN COMPOUNDS Thisapplication is a division of application Ser. No. 746,262, filed July22, 1968, now US. Pat. No. 3,580,931.

DETAILED DESCRIPTION The present invention pertains to heterocycliccarboxylic acids, processes for the production thereof, a method ofproducing a diuretic and saluretic effect as well as pharmaceuticalcompositions.

More particular, the present invention pertains to heterocycliccarboxylic acids of the Formula I R is hydrogen or lower alkyl;

X is oxygen, sulfur, the imino or the methylimino group;

Y is hydrogen, methyl, fluoro, chloro or bromo, and each of Z and Ztaken individually is hydrogen, lower alkyl, lower alkoxy, fluoro,chloro or bromo, as well as to the pharmaceutically acceptable saltsthereof with a base.

These compounds have been found to possess valuable pharmacologicalproperties. In particular, they have a diuretic and saluretic activity.These properties characterize the compounds of the invention suitablefor the treatment of disturbances which are due to insufficientexcretion of urine and of electrolytes, especially of sodium chloride.Such disturbances are the cause of oedema and hypertension. The newsubstances administered orally in low doses increase the excretion ofuria and of sodium and chlorine ions to a considerable extent.

In the heterocyclic carboxylic acids of Formula I, Z occupies the 4- or6-position and Z the 6- or 7-position of the heterocyclic ring. By theterm lower alkyl and the derivation thereof using the root alk, namelyalkoxy, is intended a group comprising a straight or branchedhydrocarbon chain of from one to four carbon atoms. Representative oflower alkyl groups are thus, e.g. the methyl, ethyl, propyl, isopropyl,butyl or tert. butyl group. Embraced by the term lower alkoxy are suchgroups as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or the sec.butoxy group.

Compounds of Formula I are produced according to a first process bydecomposing a compound of Formula II Egg-Am C Zi ni m-oomir l coon XAX iH-Am [11 wherein Am is split off. If desired, the reaction product ofFormula I is converted into a pharmaceutically acceptable salt with aninorganic or organic base in a conventional manner.

As radical of a secondary amine, Am can be, e.g. the dimethylamino,diethylamino, l-pyrrolidino, lpiperidino, l-hexahydro- 1 H-azepino orthe morpholino group.

A compound of Formula H is preferably decomposed by heating in thepresence of a weak base in a solvent containing hydroxyl groups.Examples of weak bases are sodium acetate or sodium hydrogen carbonate.Examples of solvents containing hydroxyl groups are glacial acetic acidand water.

Compounds of Formula II are produced, for example, as follows:Carboxylic acids of Formula IV, which are also starting materials forthe second process according to the invention, are condensed accordingto Friedel-Crafts in the presence of aluminum chloride in nitrobenzenewith carboxylic acid chlorides of Formula IVa RCH COCl (lVa) wherein Rhas the meaning given in Formula I, to form the corresponding 5-alkanoylderivatives. Such 5-alkanoyl derivatives are, e.g. the 5-acetyl,5-propionyl, 5- butyryl, 5-valeryl or 5-isovaleryl derivatives ofbenzofuran-2-carboxylic acid, of benzo[b]thiophene-2-carboxylic acid, ofindole-2-carboxylic acid or of l-methyl-indole-2-carboxylic acids which,optionally are sub stituted by the radicals Y, Z and/or 2 The 5-alkanoylderivatives mentioned are then converted into the corresponding Mannichderivatives with the aid of formaldehyde or paraformaldehyde and asecondary organic arrune.

Compounds of Formula I are produced by a second process according to theinvention by reacting, according to Friedel-Crafts, a compound ofFormula IV wherein X, Y, Z and Z have the meanings given in Formula I,with a carboxylic acid halide of Formula V or with a carboxylic acidanhydride of Formula VI im 0 I) wherein R has the meaning given inFormula I, and Q is halogen.

If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

As halogen, Q is preferably chlorine or bromine. Suitable catalysts forthe reaction according to Friedel- Crafts are, e.g. aluminum chloride,stannic chloride, zinc chloride, concentrated sulfuric acid, phosphoricacid, polyphosphoric acid or pyrophosphoric acid, containing hydroxylgroups. The acids are used, preferably, when a carboxylic acid anhydrideis the acylating agent. The reaction is preferably performed in asolvent, such as, e.g. aliphatic or cycloaliphatic hydrocarbons such asheptane or cyclohexane, nitrated hydrocarbons such as nitromethane,nitrocyclohexane or nitrobenzene, halogenated hydrocarbons such ascarbon tetrachloride, ethylene chloride, methylene chloride, oro-dichlorobenzene, and carbon disulfide.

Compounds of Formula II wherein X, Y, Z and Z have the meanings given inFormula I are described in the literature, e.g. benzofuran-Z-carboxylicacid [cf. R. Fittig et al., Ann. Chem. 216, 162 (1883)],benzo[blthiophene-2-carboxylic acid (cf. P. Friedlunder et al., Chem.Ber. 45, 2087 (1912)], indole-2-carboxylic acid [of W. Madelung, Chem.Ber. 45, 3521( 1912)], 4-chloroindole-2-carboxylic acid (cf. I-I.N.Rydon et al., J. Chem. Soc. 1955, 3499) and 1- methyl-indoleQ-carboxylicacid {cf E. Fischer et al., Chem. Ber. 16, 2245 (1883 Other compounds ofthis type can be produced in analogy to the literature references cited.

Compounds of Formula I are produced by a third process according to theinvention by simultaneously saponifying the ester group and splittingoff the secondary organic amine from a compound of Formula VII COOR1wherein R, X, Y, Z and Z have the meanings given in Formula I, Am hasthe meaning given in Formula II and R is a lower alkyl or the benzylgroup. If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

This simultaneous saponification and splitting reaction is preferablyperformed by shortly boiling the compound of Formula VII in an aqueousalkanol in the presence of an alkali or alkaline earth metal hydroxideor carbonate.

Compounds of Formula VII, are produced e.g. by esterifying a compound ofFormula H with a lower alkanol or benzyl alcohol. This esterificationhas to be carried out under mild conditions so that the secondary aminogroup is not split off. The compounds of Formula VII are also producedby acylating according to Friedel-Crafts a lower alkyl or benzyl esterof Formula IV with an acid chloride of Formula lVa. The so obtainedester is then converted into the corresponding Mannich derivative ofFormula VII by reaction with formaldehyde or paraformaldehyde and asecondary amine.

Compounds of Formula I are produced by a'fourth process according to theinvention by saponifying in conventional manner a compound of FormulaVIII CfHz Z1 nix-co /L]Y i -COOR1 vnr wherein R, X, Y, Z, and Z have themeanings given in Formula I and R has the meaning given in Formula VII.

If desired, the reaction product of Formula I is converted into apharrnaceutically acceptable salt with an inorganic or organic base inconventional manner.

This saponification is, e.g., carried out in a solvent containinghydroxyl groups in the presence of an alkali or alkaline earth metalhydroxyde or carbonate.

Compounds of Formula VIII are produced by heating a compound of FormulaVII in the presence of a weak base, in a solvent containing hydroxylgroups, in a way as described in the first process of this invention.Sodium acetate and sodium hydrogen carbonate which do not saponify theester function can be used as weak bases. Water or lower fatty acidssuch as glacial acetic acid can be used as solvents.

Compounds of Formula I are produced by a fifth process according to theinvention by splitting off hydrogen halide from a compound of Formula IXwherein R, X, Y, Z and Z have the meanings given in Formula I and Q hasthe meaning given in Formula V. If desired, the reaction product ofFormula I is converted into a pharmaceutically acceptable salt with aninorganic or organic base in a conventional manner.

As halogen atom Q is preferably chlorine or bromine. The elimination ofhydrogen halide is carried out e.g. by boiling the compound of FormulaIX in an organic base, such as collidine or in dimethyl formarnide.Hydrogen halide can also be eliminated by boiling a compound of FormulaIX in an organic solvent such as benzene or toluene in the presence ofsilver acetate or by boiling in dimethyl formamide in the presence oflithium bromide or carbonate.

The compounds of Formula IX used as starting materials can be producedin analogy to the second process of this invention by condensing acompound of Formula IV, according to Friedel-Crafts, in nitrobenzene inthe presence of aluminum chloride, with a carboxylic acid chloride ofFormula IXa Formula IX can also be produced by chlorinating orbrominating a compound of Formula IXb (IXa) wherein R, X, Y, Z and Zhave the meanings given in Formula I and R represents a lower alkylgroup with an alkylating agent of Formula Xa R A (Xa) wherein R has themeaning given in Formula X and A is the monovalent anion of a mineralacid, to give the ternary sulfonium compound of Formula Xb Z1 it n (tofj w v ooon x Z:

wherein R, X, Y, Z and Z have the meanings given in Formula I, R has themeaning given in Formula X and A the meaning given in Formula Xa, andboiling this compound in the presence of a weak base until the sulfoniumgroup is split off. If desired, the reaction product of Formula I isconverted into a pharmaceutically acceptable salt with an inorganic ororganic base in a conventional manner.

Alkyl halides and dialkylsulfates can be used as alkylating agents. Theelimination of the ternary sulfonium group is performed under similarconditions as the elimination of the secondary amine as described in thefirst process of this invention, i.e. by heating the compound of FormulaXb in the presence of a weak base such as sodium acetate or sodiumhydrogen carbonate in a solvent containing hydroxyl groups like water orlower fatty acids.

The compounds of Formula X can be produced e.g. by boiling, in abuffered aqueous solution of pH 7-9, a compound of Formula II, or a saltof such a compound with a hydrogenhalide, with an excess of a sodiumlower alkyl sulfide of the Formula Xc NaSR (Xc) wherein R has themeaning given in Formula X, until the secondary amine is replaced by thealkylsulfide group.

Compounds of Formula I are produced by a seventh process according tothe invention by splitting ofi the alkylsulfonyl group of a compound ofFormula XI as Z2 wherein R, X, Y, Z, and 2 have the meanings given inFormula I and R, has the meaning given in Formula X, by boiling thiscompound in the presence of a weak base in a solvent containing hydroxylgroups. Ifdesired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

Sodium acetate or sodium hydrogen carbonate can be used as weak bases.As solvents are preferably used water or lower fatty acids.

The compounds of Formula XI can be easily produced by treating acompound of Formula X in an organic solvent with a per acid or hydrogenperoxide. Per acids suitable for this oxidation are, e.g., performicacid peracetic acid or perbenzoic acid. Lower alcohols, lower ketones orlower fatty acids are convenient solvents for this reaction.

For the formation of pharmaceutically acceptable salts can be usedinorganic or organic bases such as alkali or alkaline earth hydroxides,carbonates or bicarbonates. Suitable are thus, e.g. sodium, potassium,magnesium and calcium hydroxides, carbonates or bicarbonates, as well ascholine and triethanolamine. Such salts are produced e.g. by mixing thecompound of Formula I with the equivalent amount of the desired base ina suitable solvent such as water, mixtures of water with an organicsolvent or in organic solvents alone such as methanol, ethanol orpropanol and isolating the salts formed in a conventional manner.

The compounds of the invention have been found to have valuablepharmacological properties, especially diuretic and saluretic activitiescombined with a very low order of toxicity. These favorable propertiesrender the compounds of Formula I and their pharmaceutically acceptablesalts with inorganic or organic bases suitable for the treatment ofdisturbances which are due to insuflicient excretion of urine and ofelectrolytes, particularly of sodium chloride. Such disturbances are thecause of oedema and hypertension.

The diuretic and saluretic effects of the compounds of the invention areillustratively demonstrated in dogs and rabbits. Thus it can be shown byconventional pharmacological experiments that5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid, 5-(2-methylene-butyryl)-4chloro-indole-2-carboxylic acid and5-(Z-methylene-butyryl)-4-chloro-benzo[blthiop hene-2-carboxylic acidadministered orally or parenterally in amounts of 5 mg/Kg to dogs andrabbits increase the excretion of urine and simultaneously of sodiumchloride to a considerable extent, whereby no undesirable side effectsare observed.

The new active substances or the pharmaceutically acceptable saltsthereof are preferably administered orally.

The daily dosages vary between 50 and 1,000 mg for mammals. Suitabledosage units such as dragees and tablets, preferably contain 25-500 mlof an active substance according to the invention, i.e. 20 to percent ofa compound of Formula I. They are produced by combining the activesubstance, e.g. with solid pulverulent carriers such as lactose,saccharose, sorbitol, mannitol; starches such as potato starch, maizestarch or amylopectin, also laminaria powder or citrus pulp powder;cellulose derivatives or gelatine, optionally with the addition oflubricants such as magnesium or calcium stearate or polyethyleneglycols, to form tablets or dragee cores. The latter are coated, e.g.with concentrated sugar solutions which can also contain, e.g. gumarabic, talcum andfor titanium dioxide, or with a lacquer dissolved ineasily volatile organic solvents or mixtures of solvents. Dyestufis canbe added to these coatings, e.g. to distinguish between varying dosagesof active substance.

The following examples further illustrate the production of the newcompounds of Formula I and of hitherto undescribed intermediate productsas well as the production of pharmaceutical compositions but they are byno means the sole methods of producing same. The temperatures are givenin degrees Centigrade.

EXAMPLE 1 a. 2.3 g of -butyryl-benzofuran-2-carboxylic acid, 0.5 g ofparaformaldehyde and 1.0 g of dimethylamine hydrochloride are slurriedin 20 ml of dioxan and the whole is refluxed for 5 hours while stirring.The reaction mixture is cooled and evaporated to drynws in vacuo. 30 mlof glacial acetic acid and 3.0g of anhydrous sodium acetate are added tothe crude 5-( 2- dimethyl-aminomethyl-butyryl)-benzofuran-2-carboxylicacid hydrochloride obtained and the mixture is refluxed for 2 hours. Thesolvent is then evaporated in vacuo, the residue is taken up in 50 ml ofwater and the aqueous solution is acidified with concentratedhydrochloric acid to pH 23. The hydrochloric acid suspension is stirredfor half an hour. The precipitated crystals are then filtered off,washed with water, dried in vacuo at 60 and recrystallized frombenzene/hexane. The 5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acidobtained melts at 128129.

The 5-butyryl-benzofuran-Z-carboxylic acid used as starting material isproduced as follows:

b. 5.0 g of benzofuran-2-carboxylic acid [cf. R. Fittig et al., Ann.Chem.2l6, 162 (1883)] are suspended in 20 ml of nitrobenzene and thesuspension is cooled to 0. 12.0 g of pulverized aluminum chloride areadded in portions to this suspension so that the temperature of thereaction mixture does not rise above 4.0 g of butyryl chloride are thenadded all at once. The mixture is then heated to room temperature whilestirring. Stirring is continued for 24 hours at this temperature andthen it is poured onto 100 g of ice in ml of concentrated hydrochloricacid. The hydrochloric acid suspension is extracted twice with 100 ml ofacetic acid ethyl ester each time, the acetic acid ethyl ester solutionis washed with 50 ml of water and extracted twice with 50 ml ofconcentrated sodium hydrogen carbonate solution each time. The pH of thesodium hydrogen carbonate solution is adjusted to 3 with concentratedhydrochloric acid, the mixture is stirred for 30 minutes, theprecipitated crude product is filtered off, the filter residue is driedin vacuo at 60 and recrystallized from benzene.S-butyryl-benzofuran-2-carboxylic acid is obtained, MP. l79-l8l.

EXAMPLE 2 8 g of 4-chloroindole-2-carboxylic acid (cf. l-LN. Rydon etal., J. Chem. Soc. I955, 3499) are slum'ed in 40 ml of nitrobenzene. Theslurry is cooled to 0 and 20 g of pulverized aluminum chloride are addedin portions so that the temperature never exceeds 10. The suspension iscooled to 0 and 3 g of Z-methylene butyryl chloride are added all atonce. The mixture is heated to 25 within 20 minutes, stirred for 45minutes at this temperature and then poured onto 200 g of ice and 30 mlof concentrated hydrochloric acid. The hydrochloric acid suspension isextracted twice with 100 ml of ether each time. The ether extract iswashed with water and extracted twice with 50 ml of concentrated sodiumhydrogen carbonate solution each time. The sodium hydrogen carbonatesolution is acidified with concentrated hydrochloric acid to pH 2-3 andthe precipitated crude product is extracted with ether. The ethersolution is dried over magnesium sulphate, concentrated and the residueis purified by chromatography on silica gel using benzene/ether/glacialacetic acid(900::20) as eluent. The 4-chloro-5-(2-methylene-butyryl)-indole-2-carboxylic acid obtained melts at 19 l-l92.

EXAMPLE 3 a. Crude3,4-dichloro-5-(Z-dimethylaminomethylbutyryU-indole-Z-carboxylic acidhydrochloride is obtained analogously to example 1 (a) starting from3,4- dichloro-S-butyryl-indole-Z-carboxylic acid with paraformaldehydeand dimethylamine hydrochloride. it is converted with sodium acetate andglacial acetic acid into 3,4dichloro-5-( Z-methylene-butyryl)-indole-2-carboxylic acid which, recrystallizes from benzene/acetic acid ethylester, melts at 2l0-21 1. The starting material,3,4-dichloro-S-butyryl-indole-2- carboxylic acid, is produced asfollows:

b. 29 g of 4-chloroindole-2-carboxylic acid (cf. l-l.N. Rydon et al., J.Chem. Soc. 1955, 3499) are suspended in 400 ml of ether. 15 ml ofsulphuryl chloride are added dropwise to this suspension at refluxtemperature, the addition being made within 20 minutes while stirring.The reaction mixture is stirred for another 3 hours at the sametemperature, then cooled and ml of water are added dropwise. The ethersolution is separated from the aqueous solution, the organic phase iswashed with water and extracted twice with 100 ml of saturated sodiumhydrogen carbonate solution each time. The sodium hydrogen carbonatesolution is acidified with concentrated hydrochloric acid to pH 2 andthe precipitated free carboxylic acid is filtered off, washed with waterand dried in vacuo at 60. Recrystallization from benzene/acetic heldethyl ester yields pure 3,4-dichloro-indole-Z-carboxylic acid whichmelts at 240-24 1.

c. l 1.5 g of the carboxylic acid obtained according to (b) aresuspended in 50 ml of nitrobenzene. 7.5 g of butyryl chloride are addedto this suspension, the mixture is cooled to 0 and 25 g of pulverizedaluminum chloride are added in portions so that the temperature of thereaction mixture does not exceed 10. The whole is then stirred foranother 5 hours at a reaction temperature of 25. The reaction solutionis then poured onto 200 g of ice in 40 ml of concentrated hydrochloricacid, 70 ml of benzene are added and the suspension is well stirred. Theprecipitate formed is filtered off, dried at 60 in vacuo andrecrystallized from dioxan. The 3,4-dichloro-S-butyryl-indole-Z-carboxylic acid obtained melts at 27 l-272.

EXAMPLE 4 a. Crude 1-methyl-3,4-dichloro-5-(2-dimethylaminomethyl-butyryl)-indole-2-carboxylic acid hydrochloride isobtained analogously to example 1 (a) starting from crude1-methyl-3,4-dichloro-5-butyryl-indole-2-carboxylic acid withparaformaldehyde and dimethylarnine hydrochloride. The crude product isconverted with glacial acetic acid and sodium acetate into1-methyl-3,4-dichloro-5-(2-methylene-butyryl)- indole-2-carboxylic acid.M.P. 163l64 (from benzene).

The starting material,1-methyl-3,4dichloro-5-butyryl-indole-2-carboxylic acid, is produced asfollows:

b. 29 g of 4chloroindole-2-carboxylic acid (cf. H.N. Rydon et al., J.Chem. Soc. 1955, 3499) are dissolved by gently heating in 300 ml ofacetone, 35 ml of dimethyl sulphate are added to this solution and themixture is added dropwise within 30 minutes while stirring to a lightlyboiling suspension of 45 g of finely pulverized potassium carbonate in150 ml of acetone. The whole is stirred under reflux for another 3hours. The precipitated salts are then removed from the solution byfiltration and the filtrate is concentrated in vacuo. Crudel-methyl-4-chloroindole-2-carboxylic acid methyl ester remains, to whichare added 75 ml of 4N sodium hydroxide solution, 75 ml of water and 50ml of ethanol. The mixture is refluxed for 30 minutes, cooled, washedwith ether and acidified to pH 2 with concentrated hydrochloric acid.The precipitated crystals are filtered off, washed with water and driedin vacuo at 70. The crude product is recrystallized from dioxan,whereupon the l-methyl-4-chloroindole-2-carboxylic acid melting at 252253 is obtained.

The carboxylic acid obtained is converted with sulphuryl chlorideanalogously to example 3 (b) into 1-methyl-3,4-dichloro-indole-2-carboxylic acid, M.P. 252253 (from dioxan)which is reacted with butyryl chloride analogously to example 1 (b) toform 1- methyl-3,4-dichloro-5-butyryl-indole-2-carboxylic acid (crudeproduct).

EXAMPLE 5 a. Crude4-methy1-5-(2-dimethylaminomethyl-butyryl)-benzofuran-2-carboxylic acidhydrochloride is obtained analogously to example 1a) starting from 4-methyl-S-butyryl-benzofiiran-2-carboxylic acid with paraformaldehyde anddimethylarnine hydrochloride. The crude product is converted with sodiumacetate in glacial acetic acid into4-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid whichmelts at 150l60 (from benzene/acetic acid ethyl ester).

The starting material, 4-methyl-5-butyryl-benzofuran-Z-carboxylic acid,is produced as follows:

b. A suspension of 11 g. of 2-methyl-6-hydroxybenzaldehyde [cf. 0.Anselmino, Chem. Ber. 50, 395 (1917)] and 11 g of anhydrous potassiumcarbonate in 40 ml of methylethyl ketone is stirred, refluxed and,within 15 minutes, 20 g of bromomalonic acid diethyl ester are addeddropwise. The reaction mixture is then boiled and stirred for another 7hours and then concentrated in vacuo. A solution of 10 g of potassiumhydroxide in 8 ml of water and ml of ethanol is added to the reside, thereaction mixture is refluxed for 2 hours, cooled, ml of water are addedand the ethanol is evaporated in vacuo. The resultant alkaline-aqueoussolution is acidified to pH 2-3 with 20 percent sulphuric acid. Theprecipitated crystalline crude product is filtered off, washed withwater, dried in vacuo at 60 and re-crystallized from benzene whereuponthe pure 4-methyl-benzofi1ran-2-carboxylic acid melts at 189-191.

The carboxylic acid obtained is converted into 4-methyl-S-butyryl-benzofuran-2-carboxylic acid, M.P. l67 (from benzene)with butyryl chloride in the presence of aluminum chloride analogouslyto example 1 (b).

EXAMPLE 6 4-Methyl-5-( Z-rnethyIene-butyryl)-indole-2-carboxylic acid,M.P. 194-l95 (from benzene) is obtained analogously to example 2 (a)from 4-methyl-indole-2- carboxylic acid [cf. R. Andrisano et al., CA 52,6313 (1958); Gazz. chim. ital. 87 949 (1957)] with 2- methylene-butyrylchloride in the presence of aluminum chloride in nitrobenzene.

EXAMPLE 7 a. 1 ,4-Dimethyl-5-( 2-methylene-butyryl)-indole-2- carboxylicacid, M.P. -18l (from acetic acid ethyl ester/benzene) is obtainedanalogously to example 2 (a) from 1,4-dimethyl-indole-2-carboxylic acidand 2- methylene-butyryl chloride in the presence of aluminum chloridein nitrobenzene.

The starting material, l,4-dimethyl-indole-2-carboxylic acid, isproduced as follows:

b. A suspension of 35 g of potassium carbonate in 100 ml of acetone isstirred at reflux temperature. A solution of 17.5 g of4methyl-indole-2-carboxylic acid [c.f. R. Andrisano et al., Gazz, chim.ital. 87,949 (1957)]and 25 ml of dirnethyl sulphate in 150 ml of acetoneis added dropwise to this suspension within 20 minutes. The reactionmixture is refluxed for 14 hours, cooled, the precipitate is filteredoff and washed with acetone. The filtrate is concentrated in vacuo. Theresidue, crude l,4-dimethyl-indole-2-carboxylic acid methyl ester, isrefluxed for 30 minutes with 120 ml of 2N sodium hydroxide solution and60 ml of ethanol. The solution is then cooled, the pH is adjusted to 2and the precipitated crude carboxylic acid is filtered off, washed withwater and dried in vacuo at 60. After recrystallization from acetic acidethyl ester/dioxan, 1,4-dimethyl-indole-2-carboxylic acid, M.P. 236237is obtained.

EXAMPLE 8 a. 4.0 g of S-butyryl-6-methyl-benzofuran-2-carboxylic acid,0.82 g of paraformaldehyde and 1.64 g of dimethylamino hydrochloride arerefluxed for 5 hours in 40 ml of dioxane while stirring. The reactionmixture is then evaporated in vacuo, 5.0 g of sodium acetate as well as50 ml of glacial acetic acid are added to the crude5-(2-dirnethylaminomethylbutyryl)-6-methylbenzofuran-Z-carboxylic acidhydrochloride obtained and the mixture is refluxed for 2 hours. Theglacial acetic acid is then evaporated in vacuo, the residue is taken upin 100 ml of water and the aqueous solution is acidified withconcentrated hydrochloric acid to pH 2-3. The hydrochloric acidsuspension is stirred for 1 hour at 20. The precipitated crystals arethen filtered off under suction, dissolved in acetic acid ethyl ester,the solution is dried with anhydrous magnesium sulphate and evaporatedin vacuo. The residue is recrystallized from a small quantity of aceticacid ethyl ester whereuponS-(Z-methyIene-butyryl)-6-methylbenzofuran-2-carboxylic acid isobtained. M.P. 141-142.

The starting compound, 5-butyryl-6-methyl-benzofuran-2-carboxylic acid,is produced as follows:

b. 10.0 g of 6methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers,Ann. Chem. 408, 255 (1915)] are suspended in 30 ml of nitrobenzene. 28.0g of aluminum chloride are added to the suspension in portions whilecooling with ice so that a reaction temperature of 10 is maintained. 9.0g of butyryl chloride are then added dropwise within 30 minutes at thesame temperature. The mixture is then stirred for 24 hours at 25, afterwhich it is poured into 300 g of ice and 50 m1 of concentratedhydrochloric acid and the hydrochloric acid suspension is extractedtwice with 300 ml of ether each time. The combined ether solutions arewashed with water and extracted twice with 100 ml of saturated sodiumhydrogen carbonate solution each time. The pH of the sodium hydrogencarbonate extract is adjusted to 2-3 with concentrated hydrochloric acidand the suspension formed is stirred for 1 hour at room temperature. Theprecipitated crystals are filtered off under suction, washed with waterand dissolved in acetic acid ethyl ester. The acetic acid ethyl estersolution is dried with anhydrous magnesium sulphate and concentrated invacuo. Fractional recrystallization of the residue from acetic acidethyl ester/dioxane yields 5-butyryl-6-methyl-benzofuran-2- carboxylicacid, MP. l55-l57.

EXAMPLE 9 a. Starting from 4.6 g of4,6-dimethyl-5-butyrylbenzofuran-Z-carboxylic acid, L g ofparaformaldehyde and 1.75 g of dimethylamine hydrochloride, crude4,6-dimethyl--(Z-dimethyl-aminomethyl-butyryl)-benzofuran-2-carboxylicacid hydrochloride is obtained analogously to example 1 (a). It isconverted with 5.0 g of sodium acetate and 50 ml of glacial acetic acidinto 4,6-dimethyl-5-(2-methylene-butyryl)- benzofuran-2-carboxylic acidwhich melts at 208210 (from ethanol).

b. The starting compound, 4,6-dimethyl-5-butyrylbenzofuran-Z-carboxylicacid, is produced analogously to example 1(b) from 12.3 g of4,6-dimethyl-benzofuran-2-carboxylic acid (cf. F .M. Dean et al., J.Chem. Soc. 1953, 1250-1261) and 10.0 g of butyryl chloride with 25.0 gof aluminum chloride. After recrystallization from benzene/hexane, the4,6-dirnethyl-5-butyrylbenzofuran-Z-carboxylic acid melts at 190l 92.

EXAMPLE a. Starting from 5.6 g of 4-chloro-5-butyryl-benzo[b]thiophene-2-carboxy1ic acid with 1.2 g of paraformaldehyde and 2.5 gof dimethylamine hydrochloride,

crude 4-chloro-5-(Z-dimethyl-aminomethyl-butyryl)-benzo[b]thiophene-2-carboxylic acid hydrochloride is obtainedanalogously to example 1 (a). It is converted with 1.7 g of sodiumacetate and 17 ml of glacial acetic acid into 4-chloro-5-(2-methylene-butyry1)- benzo[b]thiophene-2-carboxylic acid which melts at23924l (from ethyl acetate/dioxane).

The 4-chloro-5-butyryl-benzo[b]thiophene-2-carboxylic acid used asstarting material is produced as follows:

b. 22.5 g of o-chlorobenzaldehyde are added dropwise within 10 rninutesto a boiling mixture of 20.0 g of rhodanine, 37.5 g of anhydrous sodiumacetate and 100 ml of glacial acetic acid. The reaction mixture is thenstirred for another 20 minutes at the same temperature whereupon it ispoured into 3 liters of ice water. The crude5-(o-chlorobenzylidene)-rhodanine precipitates. The crystals arefiltered ofi under suction and washed with 500 ml of water. The moistproduct is then added to a solution of 25.0 g of sodium hydroxide in 1.8liters of water. The reaction mixture is dissolved while stirring,heated to within 10 minutes and kept at this temperature for 10 minutes.The solution is cooled to 10 and 65 ml of concentrated hydrochloric acidare added. The crude o-chloro-a-mercapto-cinnamic acid precipitates. Thecrude product is filtered off under suction, washed with water anddissolved in 700 ml of ether. The ether solution is dried with anhydrousmagnesium sulphate and evaporated in vacuo. The residue is added inportions to a solution of 60 g of iodine in 200 ml of nitrobenzene whichhas been heated to 180, the addition being made within 2 minutes. Thereaction mixture is stirred for another 2 minutes, then poured onto 1 kgof ice and the suspension obtained is extracted twice with 500 ml ofchloroform each time. The chloroform extract is shaken twice with 100 mlof 2N sodium hydroxide solution each time, the aqueous alkaline solutionis decolored with active charcoal and saturated sodium sulphitesolution, the suspension is filtered and the pH of the filtrate isadjusted with concentrated hydrochloric acid to 2-3. The-crudecarboxylic acid precipitates. It is filtered off under suction, washedwith water and recrystallized from dioxane/acetic acid ethyl ester,whereupon the pure 4-chlorobenzo[b] thiophene-2-carboxylic acid obtainedmelts at 246-24 7.

c. 9.0 g of the carboxylic acid obtained according to (b) are convertedanalogously to example 1 (b) into 4-chloro-5-butyryl-benzo[blthiophene-Z-carboxylic acid which melts at217-2l9 (from acetic acid ethyl ester). The conversion is performedaccording to Friedel-Crafts with 8.0 g of butyryl chloride in thepresence of 25.0 g of aluminum chloride.

EXAMPLEll a. Crude 6-methyl-5-[( 2-dimethylaminomethyl)-propionyl]benzofuran-2-carboxylic acid hydrochloride is obtained by theprocess described in example 8 (a) starting from 4.6 g of6-methyl-5-propionyl-benzofuran-Z-carboxylic acid, 0.7 g ofparaformaldehyde and 1.9 g of dimethylamine hydrochloride. It isconverted with 2.5 g of sodium acetate in 25 ml of glacial acetic acidinto 6-methyl-5-(Z-methylene-propionyl)-benzofiiran-2-carboxylic acid,MP. ll 86 (recrystallized from acetic acid ethyl ester).

b. The starting material, -propionyl-2-methylbenzofuran-Z-carboxylicacid is produced analogously to example 8 (b) from6-methyl-ben2ofuran-2-carboxylic acid (cf. K. von Auwers, Ann. Chem. 408(1915) 255) with propionyl chloride and aluminum chloride innitrobenzene. After recrystallization from dioxane, it melts at l80l 82.

EXAMPLE 12 a. Crude 6-methyl-5-[(2-dimethylaminomethyl)-valeroyl]-benzofuran-2-carboxylic acid hydrochloride is obtainedaccording to example 8 (a) starting from 6-methyl-5-valeroyl-benzofuran-Z-carboxylic acid, paraforrnaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into6-methyl-5-(2-methylene-valeroyl)-benzofuran-2-carboxylic acid. M.P.l60-162 (recrystallized from benzene ethyl acetate).

b. The starting material, 6-methyl-5-valeroylbenzofuran-Z-carboxylicacid is produced analogously to example 8 (b) from6-methyl-benzofuran-2-carboxylic acid (cf. K. von Auwers, Ann. Chem. 408(1915) 255) with valeroyl chloride and aluminum chloride innitrobenzene. It melts at l54-l55 (recrystallized from acetic acid ethylester).

EXAMPLE 13 a. Crude 6-methyl-5-[2-dimethylaminomethyl-3-methyl-butyryl]-benzofuran-2-carboxylic acid dihydrochloride is obtainedanalogously to example l (a) starting from6-methyl-5-(3-methyl-butyryl)- benzofuran-Z-carboxylic acid withparaformaldehyde and dimethylamine hydrochloride. It is converted withsodium acetate in glacial acetic acid into 6-methyl-5-(2-methylene-C-methyl-butyryl)-benzofuran-2-car-' boxylic acid, M.P.153l54 (recrystallized from acetic acid ethyl ester).

b. The starting compound,6-methyl-5-(3-methyl-butyryl)-benzofuran-2-carboxylic acid, is producedanalogously to example 8 (b) from 6-methyl-benzofuran-Z-carboxylic acid(cf. K. von Auwers, Ann. Chem. 408 (1915) 255) with isovaleroyl chlorideand aluminum chloride in nitrobenzene. It melts at 154l56(recrystallized from ethyl acetate).

EXAMPLE 14 1i EXAMPLE 1s a. Crude 6-methoxy-5-[(2-dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic acid hydrochloride is obtainedanalogously to example 8 (a) starting from 6-methoxy-5-butyryl-benzofuran-2-carboxylic acid, parafonnaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into6-methoxy-5-(2-methylene-butyryl)-benzofuran-Z-carboxylic acid, M.P.l53l54 (recrystallized from benzene).

b. The starting compound, 6-methoxy-5-butyrylbenzofuran-Z-carboxylicacid is produced from 6- methoxy-benzofuran-2-carboxylic acid (cf. W.Will and P. Beck, Ber. 19, 1777 (1886) with butyryl chloride andaluminum chloride in nitrobenzene. It melts at l89-l90 (recrystallizedfrom ethyl acetate).

EXAMPLE 16 a. Starting from 6-ethoxy-5-butyryl-benzofuran-2- carboxylicacid, paraformaldehyde and dimethylamine hydrochloride, crude6-ethoxy-5-[ (2- dirnethylaminomethyl)-butyryl]-benzofuran-2-carboxylicacid hydrochloride is obtained analogously to example 8 (a). It isconverted with sodium acetate in glacial acetic acid into6-ethoxy-5-(2-methylene-butyryl)- benzofuran-2-carboxylic acid, M.P.143l44 (recrystallized from ethanol water).

b. The starting compound, 6-ethoxy-5-butyrylbenzofuran-Z-carboxylicacid, is produced analogously to example 8 (b) from6-ethoxy-benzofuran-2-carboxylic acid (cf. W. Will and P. Beck, Ber. 19(1886) 1777) with butyric acid chloride and aluminum chloride innitrobenzene. The compound melts at 203205 (recrystallized fromethanol).

EXAMPLE 17 a. Crude6-ethyl-5-[(2-dimethylaminomethyl)-butyryl]-benzo-furan-2-carboxylicacid hydrochloride is obtained analogously to example 8 (a) from6-ethyl-5- butyryl-benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into 6-ethyl-5-(Z-methyIene-butyryl)-benzofuran-2-carboxylic acid, MP. 12 ll22(recrystallized from benzene).

b. The starting compound, 6-ethyl-5-butyrylbenzofuran-Z-carboxylic acidis produced analogously to example 8 (b) from6-ethyl-benzofuran-2-carboxylic acid with butyric acid chloride andaluminum chloride in niu'obenzene.6-Ethyl-5-butyryl-benzofuran-2-carboxylic acid melts at l52153(recrystallized from acetic acid ethyl ester).

6-Ethyl-benzofuran-2-carboxylic produced as follows:

c. 50.0 g of m-ethylphenol, 55.0 g of maleic acid and ml of concentratedsulphuric acid are slowly heated to while stirring and stirring iscontinued at this temperature for 20 minutes. The reaction mixture isthen poured onto 2 kg of ice and extracted twice with 500 ml of ethereach time. The combined other extracts are washed with 200 ml of waterand 200 ml of concentrated aqueous sodium hydrogen carbonate solution,dried over magnesium sulphate and concentrated. The residue, crude7-ethyl coumarin, is used as crude product.

acid is also d. 30.4 g of 7-ethyl coumarin are dissolved in 40 mi ofchloroform and 29.0 g of bromine in 20 ml of chloroform are addeddropwise while stirring. The temperature of the reaction mixture is keptbetween 20 and 25 by occasional cooling in an ice bath. The reactionmixture is then stirred for another 20 minutes at room temperature andconcentrated at 50 under reduced pressure. The residue is added inportions to a solution of 80.0 g of potassium hydroxide in i60 ml ofethanol, which solution has been heated to 30, and the reactiontemperature is kept at 30-40 by cooling. The reaction mixture is thenfor 30 minutes at room temperature and for 30 minutes at roomtemperature and for 30 minutes at 80, after which it is poured into 1liter of ice water. The aqueous, alkaline solution is washed twice with300 ml of ether each time, acidified with concentrated hydrochloric acidto pH 2-3 and the precipitated crude product is filtered ofl" undersuction. The crude product is recrystallized from ethanol and dried invacuo at 80 whereupon the 6-ethyl-benzofuran-Z-carboxylic acid obtainedmelts at l 52-154.

EXAMPLE 18 a. Crude6-chloro-5-[(2-dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylicacid is obtained analogously to example 8 (a) starting from 1.0 g of 6-chloro--butyryl-benzofuran-2-carboxylic acid, 0.16 g of paraformaldehydeand 0.385 g of dimethylamine hydrochloride. It is converted with sodiumacetate in glacial acetic acid into S-(Z-methylene-butyryD-G-chloro-benzofuran-2-carboxylic acid. Recrystallized from benzene/aceticacid ethyl ester, it melts at l88-189.

The starting compound, 6-chloro-5-butyryl-benzofuran-Z-carboxylic acid,is produced as follows:

b. 80 g of 2-chloro-4-hydroxy-butyrophenone (cf. Belgian Pat. No.612,755) are slurried in 400 ml of water, and 100 ml of 4N sodiumhydroxide solution are added. A clear solution is formed. 20 g of sodiumborohydride are added and the whole is stirred for 5 hours at roomtemperature. The solution is then cooled with ice and hydrochloric acidis added dropwise until a pH of 3-4 has been attained. The suspension isstirred for another half hour, and then the crystals obtained of3-chloro-4(l-hydroxybutyl)-phenol are filtered off under suction. Theyare used immediately in the crude state.

c. The moist crystal mass of 3-chloro-4-( l-hydroxybutyl)-phenol isadded to a solution of 200 g of sodium hydroxide in 500 ml of water, thesolution formed is heated to 70 and 150 g of chloroform are addeddropwise within 2 hours. During the addition, the temperature of thereaction mixture must be 70-80. The mixture is stirred for 20 minutes at70 and then cooled to room temperature. The yellow crystal mass whichprecipitates, which consists of the sodium salt of 3- chloro-4-(l-hydroxy-butyl )-2-formyl-phenol, is filtered off under suction. Thepl-i of the filtrate is adjusted to 2-3 with concentrated hydrochloricacid, the filtrate is extracted twice with 100 ml of ether each time andthe combined ether extracts are washed with 100 m1 of water, after whichthey are stirred for 10 hours with 200 ml of concentrated sodiumhydrogen sulphite solution. The crystals obtained, which consist of thebisulphite adduct of 3-chloro-4-(i -hydroxy-butyl)-6formy1- phenol, andfiltered 011 under suction and washed first with 50 ml of ether and thenwith 50 ml of water. The crystals are then slurried in ml of water, 100ml of ether are poured in, 15 ml of concentrated hydrochloric acid areadded and the mixture is stirred for 2 hours whereupon the crystalsdissolve. The ether phase is removed, washed with 50 ml of water, driedover magnesium sulphate and concentrated. The residue consists of 6.5 gof 3-chloro-4-( l-hydroxy-butyl)-6-formyl phenol, which is used in thecrude state.

(1. 6.5 g of crude 3-chloro-4-(1-hydroxy-butyl)-6-formyl phenol aredissolved in 30 ml of methylethyl ketone, 4.0 g of potassium carbonateare added and the mixture is refluxed while stirring. 8 g ofbromomalonic acid diethyl ether are then added dropwise within 10minutes whereupon the reaction mixture is refluxed for 5 hours whilestirring. The solvent is then distilled off, the residue is talcen up in50 m1 of water, concentrated hydrochloric acid is added until pH 3 isattained and the mixture is extracted twice with 100 ml of ether eachtime. The ether solutions are washed with 100 ml of water, dried overmagnesium sulphate and concentrated. A solution of 5 g of potassiumhydroxide, 5 ml of water and 50 ml of ethanol is added to the residueand the mixture is refluxed for 2 hours. 200 ml of water are then addedand the aqueous-alkaline solution is washed twice with 100 ml of ethereach time. The aqueous solution is acidified with concentratedhydrochloric acid and extracted twice with 100 ml of ether each time.The ether extracts are dried and concentrated. On standing, the residuecrystallizes and is recrystallized from benzene. in this way, 1.8 g of6- chloro-5-( 1-hydroxy-butyl)-benzofiiran-2-carboxylic acid, M.P. 194l96, are obtained.

e. 1.8 g of 6-chl0ro-5-( l-hydroxy-butyl)-benzofuran- Z-carboxylic acidare dissolved in 20 m1 of acetone, the solution is cooled to 0 and asolution of 0.54 g of CrO in 0.5 ml of concentrated sulphuric acid and1.5 ml of water is added. The reaction mixture is stirred for 30minutes, then distributed with 100 ml of ether and 100 ml of water, theether layer is dried over magnesium sulphate and concentrated. Theresidue is recrystallized from benzene/ethyl acetate and yields 1.2 g of5- butyryl-6-chloro-benzofuran-2-carboxylic acid which melts at 214-215.

EXAMPLE 19 a. Starting from 3.6 g of4-chloro-5-butyryl-benzofuran-Z-carboxylic acid, 0.48 g ofparaformaldehyde and 1.15 g of dimethylamine hydrochloride, crude 4-chloro-5-[2-(dimethylamino-methyl)-butyryl]- benzofuran-Z-carboxylicacid hydrochloride is obtained analogously to example 8 (b). It isconverted with 2.0g of sodium acetate and 20 ml of glacial acetic acidinto 4-chloro-5-(Z-methylene-butyryl)-benzofuran-Z-carboxylic acid, MP.156-l58 (recrystallized from benzene/ethyl acetate).

The 4-chloro-5-butyryl-benzofuran-2-carboxylic acid used as startingmaterial is produced as follows:

b. The crude sodium salt of 3-chloro-4-(l-hydroxybutyl)-2-formyl phenolobtained in example 18 (c) as side product is slurried in 200 ml ofwater, the pH is adjusted to 3 with hydrochloric acid and the slurry isextracted twice with 100 m1 of ether each time. The ether extracts arewashed with 100 ml of water, dried over l7 magnesium sulphate andconcentrated. The residue, cmde 3-chloro-4-( l-hydroxy-butyD-Z-forrnylphenol (30 g) is used in the crude state.

c. 8.2 g of 4-chloro-5-( l-hydroxy-butyD-benzofuran- 2-carboxylic acidare obtained analogously to example 18 (d) from 30 g of 3chloro-4-(l-hydroxy-butyl)-2- formyl phenol with 20 g of potassiumcarbonate and 30 g of bromomalonic acid diethyl ester in 100 ml ofmethylethyl ketone. Recrystallized from benzene/acetic acid ethyl ester,the compound melts at 173-l75.

d. 4.5 g of 4-chloro-5-butyryl-benzofuran-2-carboxylic acid are obtainedanalogously to example 18 (e) from 7.6 g of 4-chloro-5-(l-hydroxy-butyl)-benzofuran-Z-carboxylic acid in 80 ml of acetone with asolution of 2.2 g of chromium trioxide in 6 ml of water and 2 ml ofconcentrated sulphuric acid. Recrystallized from benzene/ethyl acetate,the compound melts at l33-134.

EXAMPLE 20 a. 7.2 g of 3,6-dimethyl--butyryl-benzofi1ran-2-carboxylicacid methyl ester and 3.3 g of dimethylarnine hydrochloride are meltedand the melt is stirred for 2 hours at 140. The melt obtained consistsof crude 3,6- dimethyl-5-(Z-dimethylamino-methyl-butyryl)-benzofuran-Z-carboxylic acid methyl ester hydrochloride. This isrefluxed for minutes with a solution of 80 ml of l N sodium hydroxidesolution and 80 ml of ethanol and, after dilution with 300 ml of icewater, it is acidified to pH 3 with concentrated hydrochloric cid. Theprecipitate formed is filtered off under suction and, after drying invacuo, it is purified by chromatographing over silica gel. The3,6-dimethyl- 5-(Z-methyIene-butyryl)-benzofuran-2-carboxylic acid, whenrecrystallized from benzene/heptane, melts at l52-154.

The 3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid methyl esterused as starting material is produced as follows:

b. 10.4 g of 3,6-dirnethyl-5-butyryl-benzofuran-2- carboxylic acid areadded in portions over a period of 30 minutes to a boiling slurry of 7 gof potassium carbonate in 80 ml of acetone. Simultaneously a solution of5 ml of dirnethyl sulphate in 30 m1 of acetone is added to the reactionmixture from a dropping funnel. On completion of the addition, themixture is refluxed for another 3 hours while stirring, then cooled, theprecipitate is filtered off under suction and is washed with 50 ml ofacetone. The filtrate and washing liquor are combined and evaporated andthe residue is recrystallized from carbon tetrachloride/heptane. The3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid methyl ester formedmelts at 10 l-l 05.

c. The 3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid is obtainedanalogously to example 8 (b) from 3,6-dimethyl-benzo-furan-Z-carboxylicacid (cf. Fries and Finkewirth, Chem. Ann. 362, (1908) 50) with butyricacid chloride and aluminum chloride in nitrobenzene. The compound meltsat l85l87 (recrystallized from benzene/ethyl acetate).

EXAMPLE 21 a. 0.5 g of6-methyl-5-[2-(methylthiomethyl)-butyryll-benzofuran-Z-carboxylic acidare dissolved in 5 ml of acetone, 0.5 g of dirnethyl sulphate are addedand the solution is left to stand for 3 days at room temperature. Thesolvent is then evaporated under reduced pressure and the residue,consisting of crude 6-methyl-5-[2-(dimethyl-thioniummethyl)-butyryl]-benzofuran- 2-carboxylic acidmethyl sulphate, is dissolved in 5 ml of water, 2.5 ml of saturatedsodium hydrogen carbonate solution are added to the solution formed andthe reaction mixture is heated for 1 hour in a steam bath. The cooledsolution is then acidified to pH 2-3 with hydrochloric acid, stirred forhalf an hour at room temperature and the precipitated crystals arefiltered off under suction, dried and recrystallized from benzene. 0.3 gof 6-methyl-5-[2-(methylene)-butyryl]- benzofuran-Z-carboxylic acid,M.P. 14ll42, are obtained.

The 6-methyl-5-[2-(methyl thiomethyl)-butyryl]- benzofran-Z-carboxylicacid used as starting material is produced as follows:

b. 6.8 g of 6-methyl-5-[2-(dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic acid hydrochloride (M.P. 187-l88) aredissolved in 200 ml of water, 4.04 g of sodium hydrogen carbonate areadded in portions to the solution and a constant stream of methylmercaptan is bubbled through the mixture. While continuing theintroduction of methyl mercaptan, the mixture is heated to and is keptfor 2 hours at this temperature whereupon the stream of gas is cut offand the solution is cooled. The pH of the solution is adjusted to 2-3with concentrated hydrochloric acid and the precipitate formed isfiltered ofl under suction, dried in vacuo and recrystallized from asmall amount of acetic acid ethyl ester. In this way, 5.2 g of6-methyl-5-[2- (methylthiomethyl)-butyryl]-benzofuran-2-carboxylic acid,M.P. l51-l52, are obtained.

EXAMPLE 22 a. 10 ml of water and 5 ml of a saturated sodium hydrogencarbonate solution are added to 6-methy1-5-[Z-(methylsulphonyl-methyl)-butyryl]-benzofuran-2- carboxylic acid andthen the solution is refluxed for 1% hours. It is allowed to cool andthe solution is acidified to pH 2-3 with concentrated hydrochloric acid.The mixture is stirred for another 30 minutes and then the precipitatedcrystals are filtered off under suction, dried in vacuo andrecrystallized from benzene. In this way, 0.5 g of6-methyl-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid, M.P.l41l42 are obtained.

The6-methyl-5-[2-methyl-sulphonylmethyl)-butyryl]-benzo-furan-2-carboxylicacid used as starting material is produced as follows:

b. 3.1 g of6-methyl-5-[2-(methylthiomethyl)-butyryl]-benzofuran-2-carboxylic acid(production see example 21) are slurried in 15 ml of glacial acetic acidand 3.6 g of 40 percent peracetic acid are so added dropwise to themixture while cooling with ice that the reaction temperature remainsbetween 15 and 20. The reaction mixture is then stirred for 15 hours atroom temperature and the precipitated crystal mass is filtered off undersuction. Recrystallized from ethyl acetate/dioxane, 2.8 g of6-methyl-5-[2-(methylsulphonylmethyl)-butyryl]benzofuran-2-carboxylicacid, M.P. 201-203, are obtained.

L EXAMPLE 23 a. A solution of 6-methyl-5-(2-methylene-butyryl)-benzofuran-Z-carboxylic acid methyl ester in ml of ethanol is heated toreflux temperature, 2 ml of 1N sodium hydroxide solution are added andthe mixture is refluxed for another minute whereupon it is diluted with70 ml of ice water. The solution is then washed with 50 ml of ether, thepH of the aqueous-alkaline phase is adjusted to 2-3 with hydrochloricacid and the mixture is stirred for 30 minutes. The precipitate formedis filtered off under suction, dried in vacuo and recrystallized frombenzene. in this way, 0.4 g of 6-methyl-5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid, M.P.l4l-142, are obtained.

The 6-methyl-5-(2-methylenebutyryl)-benzofuran- 2-carboxylic acid methylester used as starting material can be produced as follows:

b. 5.0 g of anhydrous potassium carbonate are slurried in 20 ml ofacetone and the slurry is brought to reflux temperature. A solution of7.5 g of 6-methyl-5- butyryl-benzofuran-Z-carboxylic acid and 3.75 ml ofdimethyl sulphate in 70 ml of acetone is added dropwise to thissuspension within minutes whereupon the reaction mixture is refluxed foranother hour and cooled. insoluble salts are then filtered 05, theacetone solution is concentrated and the residue is recrystallized frommethanol. 7.3 g of 6-methyl-5-butyrylbenzofuran-Z-carboxylic acid methylester, M.P. 9l92, are obtained in this way.

c. 5.5 g of the 6-methyl-5-butyryl-benzofuran-2-carboxylic acid methylester produced in (b) above are refluxed for 24 hours with 1.2 g ofparaformaldehyde and 3.2 g of dimethylamine hydrochloride in 12 ml ofmethanol. The methanol is then evaporated, 30 ml of acetic acid ethylester are added to the residue which is then left to stand for 2 days ina refrigerator. The crystal mass so obtained is then filtered off andrecrystallized from acetonitrile whereupon 2.4 g of 6- methyl-5-[ 2-(dimethylaminomethyl )-butyryl]- benzofuran-Z-carboxylic acid methylhydrochloride, M.P. l76l 78, are obtained.

d. l .2 g of the 6-methyl-5-[ 2-(dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic acid methyl esterhydrochloride are refluxed for 2 hours with 1.2 g of sodium acetate andml of glacial acetic acid. The glacial acetic acid is then evaporated ina rotary evaporator and the residue is distributed between 100 ml ofwater and 100 ml of ether. After washing the ether phase with 100 ml ofwater, it is removed, dried with 100 ml of saturated sodium hydrogencarbonate solution over magnesium sulphate and concentrated. The residueis recrystallized from methanol and yields 0.6 g of 6-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid methyl ester, M.P. 8586.

EXAMPLE 24 a. 1.2 g of6-methyl-5-(2-bromo-2-methyl-propionyl)-benzofuran-2-carboxylic acid in80 ml of benzene are stirred with 1.8 g of mercury acetate for 4 hoursunder reflux. The reaction mixture is then poured into a mixture of 100g of ice and 10 ml of concentrated hydrochloric acid, well stirred andthe precipitate ester formed, consisting of mercury bromide and mercurychloride, is filtered off. The residue is washed with 100 ml of aceticacid ethyl ester. The filtrate is then put into a separating funnel, theorganic phase is removed, washed with 50 ml of water, dried overmagnesium sulphate and concentrated. The residue is recrystallized frombenzene and G-methyI-S-(Z-methylenepropionyl)-benzofiiran-2-carboxylicacid, M.P. ll86.

The starting material, 6-methyl-5-(2-bromo-2-methyl-propionyl)-benzofuran-2-carboxylic acid, is produced as follows:

b. 3.0 g of 6-methyl-S-isobutyryl-benzofuran-Z-carboxylic acid aredissolved in 30 ml of glacial acetic acid and 0.7 ml of bromine areadded dropwise within 15 minutes to this solution at 50. The whole isstirred for another 15 minutes at the same temperature, after which theglacial acetic acid is evaporated in a rotary evaporator and the residueis recrystallized from ethyl acetate/dioxane. 3.65 g of6-methyl-5-(2-bromo-2- methyl-propionyl)-benzofuran-2-carboxylic acid,M.P. 231233, are obtained in this way.

c. The 6-methyl-5-isobutyryl-benzofuran-2-carboxylic acid is producedanalogously to example 8 (b) from 6-methyl-benzofi1ran-2-carboxylic acid(cf. K. von Auwers, Ann. Chem. 408, (1915) 255) with isobutyryl chlorideand aluminum chloride in nitrobenzene. It melts at 174175(recrystallized from methylethyl ketone).

The following Examples illustrate the production of tablets and dragees:

EXAMPLE 25 1,000 g of 4-chloro-5-(Z-methylene-butyryl)-indole-2-carboxylic acid are mixed with 550 g of lactose and 292 g of potatostarch, the mixture is moistened with an aqueous solution of 8 g ofgelatine and granulated through a sieve. After drying, 60 g of potatostarch, 60 g of talcum, 10 g of magnesium stearate and 20 g of colloidalsilicon dioxide are mixed in and the mixture is pressed into 10,000tablets each weighing 200 mg and containing mg of active substance. ifdesired, the tablets can be grooved for better adaptation of the dosage.

EXAMPLE 26 A granulate is produced from 1,000 g of 5-(2-methylene-butyryl)-benzofuran-2-carboxy1ic acid, 379 g of lactose andthe aqueous solution of 6 g of gelatine. After drying, the granulate ismixed with 10 g of colloidal silicon dioxide, 40 g of talcum, 60 g ofpotato starch and 5 g of magnesium stearate and the mixture is pressedinto 10,000 dragee cores. These are then coated with a concentratedsyrup consisting of 533.5 g of crystallized saccharose, 20 g of shellac,75 g of gum arabic, 250 g of talcum, 20 g of colloidal silicon dioxideand 1.5 g of dyestuff, and dried. The dragees obtained each weigh 240 mgand contain 100 mg of active substance.

What we claim is:

1. The method of producing diuresis and saluresis in mammals whichmethod comprises administering to said mammal a diuretically andsaluretically effective amount of a compound of the Formula I CH: Z1 nLCOWY wherein R is hydrogen or lower alkyl;

Y is hydrogen, methyl, fluoro, chloro or bromo; and

dosage unit form of a compoundof Formula I each of Z and Z, takenindividually is hydrogen,

lower alkyl, lower alkoxy, fluoro, chloro or bromo; or of apharmaceutically acceptable salt of said compound with a base.

2. The method according to claim 1 wherein said compound is6-methyl-5-(2-methylene-propionyl)- benzofuran-Z-carboxylic acid.

3. The method according to claim 1 wherein said compound is6methyl-5-(2-methylene-propionyl)- benzofuran-2-carboxylic acid.

4. The method according to claim 1 wherein said compound is6-methyl-5-(Z-methylene-valery l benzofuran-)-benzomran-2-carboxylicacid.

5. The method according to claim 1 wherein said compound is6-methyl-5-(2-methylene-3-methyl-butyryl)-benzofuran-2-carboxylic acid.

6. The method according to claim 1 wherein said compound is3,6-dirnethyl-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid.

7. The method according to claim 1 wherein said compound is6-ethyl-5-(2-methylene-butyryl)-benzofuran-Z-carboxylic acid.

8. The method according to claim 1 wherein said compound is6-methoxy-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid.

9. The method according to claim 1 wherein said compound is4-chloro-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid.

10. The method according to claim 1 wherein said compound is6-chloro-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid.

11. The pharmaceutical composition comprising a combination in dosageunit form of a pharmaceutical carrier and an amount sufficient toproduce a diuretic and a saluretic effect upon administration of saidwherein R is hydrogen or lower alkyl;

Y is hydrogen, methyl, fluoro, chloro or bromo; and each of Z and Ltaken individually is hydrogen, lower alkyl, lower alkoxy, fluoro,chloro or bromo; or of a pharmaceutically acceptable salt of saidcompound with a base.

12. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-methyl-5-(2- methylene-butyryl)-benzofiiran-2-carboxylicacid.

13. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-methyl-5-(2- methylene-propionyl)-benzofuran-2-carboxylicacid.

14. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-methyl-5-(2- l y fli e fiii rinic efiili l fig iiionaccording to claim 11 wherein said compound is 6-methyl-5-(2-methylene-3-methyl-butyryl)-benzofuran-2-carboxylic acid.

16. The pharmaceutical composition according to claim 11 wherein saidcompound is 3,6-dimethyl-5-(2-methylene-butyryl)-benzofura.n-2-carboxylic acid.

17. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-ethyl-5-(2- methylene-butyryl)-benzofuran-2-carboxylicacid.

18. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-methoxy-5-(2- methylene-butyryl)-benzofuran-2-carboxylicacid.

19. The pharmaceutical composition according to claim 11 wherein saidcompound is 4-chloro-5-(2- methylene-benzofuran-2-carboxylic acid.

20. The pharmaceutical composition according to claim 11 wherein saidcompound is 6-chloro-5-(2- methylene-butyryl)-benzofuran-2-carboxylicacid.

I L-266O DIV III S TED STAS PATENT @FFEQE csririmrs or ssscri Patent No.32 25 Dated August 1, 1972 Inventor s) JANOS ZERGENYI ET AL It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Cover page, left column, insert [30] Foreign Application Priority Data,

July 28, 1967 Switzerland lO76 L/67 September 29, 1967 Switzerland13637/67 after "[72] Inventors: Janos" delete "Zerginyi" and insertZERGENYI Signed and sealed this 5th day of November 1974.

(SEAL) Attest;

McCoy in GKBSGN JR. c. MARSHALL 10mm Attesting Officer Commissioner ofPatents UNITED STATES PATENT OFFECE CERTIFICATE OF CGRRECTIGN Patent No.3, 681, 502 Dated August 1, 197;

Inventor(s) Janos Zergirgi et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 22, claim lLr, line 2L after "-valeryl)" insert -benZofuran-Signed and sealed this 19th day of March 197A.

(SEAL) Attest:

c. MARSHALL DANN EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer FORM PO-105O (10-69) V USCQMMDC 603754369 u.s. GOVERNMENT PRINTING oFFlc: I969 o-ase-au.

2. The method according to claim 1 wherein said compound is6-methyl-5-(2-methylene-propionyl)-benzofuran-2-carboxylic acid.
 3. Themethod according to claim 1 wherein said compound is6-methyl-5-(2-methylene-propionyl)-benzofuran-2-carboxylic acid.
 4. Themethod according to claim 1 wherein said compound is6-methyl-5-(2-methylene-valery 1 )-benzofuran-)-benzofuran-2-carboxylicacid.
 5. The method according to claim 1 wherein said compound is6-methyl-5-(2-methylene-3-methyl-butyryl)-benzofuran-2-carboxylic acid.6. The method according to claim 1 wherein said compound is3,6-dimethyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid. 7.The method according to claim 1 wherein said compound is6-ethyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 8. Themethod according to claim 1 wherein said compound is6-methoxy-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 9. Themethod according to claim 1 wherein said compound is4-chloro-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 10. Themethod according to claim 1 wherein said compound is6-chloro-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 11. Thepharmaceutical composition comprising a combination in dosage unit formof a pharmaceutical carrier and an amount sufficient to produce adiuretic and a saluretic effect upon administration of said dosage unitform of a compound of Formula I wherein R is hydrogen or lower alkyl; Yis hydrogen, methyl, fluoro, chloro or bromo; and each of Z1 and Z2taken individually is hydrogen, lower alkyl, lower alkoxy, fluoro,chloro or bromo; or of a pharmaceutically acceptable salt of saidcompound with a base.
 12. The pharmaceutical composition according toclaim 11 wherein said compound is6-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 13. Thepharmaceutical composition according to claim 11 wherein said compoundis 6-methyl-5-(2-methylene-propionyl)-benzofuran-2-carboxylic acid. 14.The pharmaceutical composition according to claim 11 wherein saidcompound is 6-methyl-5-(2-methylene-valeryl ) 2-carboxylic acid.
 15. Thepharmaceutical composition according to claim 11 wherein said compoundis 6-methyl-5-(2-methylene-3-methyl-butyryl)-benzofuran-2-carboxylicacid.
 16. The pharmaceutical composition according to claim 11 whereinsaid compound is3,6-dimethyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid. 17.The pharmaceutical composition according to claim 11 wherein saidcompound is 6-ethyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylicacid.
 18. The pharmaceutical composition according to claim 11 whereinsaid compound is6-methoxy-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 19. Thepharmaceutical composition according to claim 11 wherein said compoundis 4-chloro-5-(2-methylene-benzofuran-2-carboxylic acid.
 20. Thepharmaceutical composition according to claim 11 wherein said compoundis 6-chloro-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.